Japanese Laid-open (KOKAI) Patent Application, KOKAI No. 92959/1993 broadly discloses a class of compounds represented by formula (A) below: ##STR2## in which R.sub.1 and R.sub.2 may be same or different, and each signifies hydrogen atom, lower alkyl or substituted lower alkyl group, etc.
R.sub.3 may be same or different and each signifies hydrogen atom or lower alkyl, etc. PA1 R.sub.5 may be same or different and each signifies hydrogen atom, halogen atom, lower alkoxy, amino, mono- or di-substituted amino group, etc. PA1 Het signifies a monocyclic heteroaryl or di-cyclic heteroaryl other than 1H-indazolyl group, PA1 q is 0, 1 or 2, PA1 s is 1, 2 or 3, PA1 B signifies --CXNR.sub.6 (CH.sub.2).sub.r --, etc. in which R.sub.6 signifies hydrogen atom or lower alkyl, etc. PA1 X signifies oxygen or sulfur atom and r is 0, 1, 2 or 3, PA1 m is 1, 2, 3 or 4, and PA1 n is 1, 2 or 3!, PA1 a selective dopamine D.sub.2 receptor antagonist which has been clinically used as an antiemetic or gastrointestinal motility improving agent; PA1 a selective serotonin S.sub.3 receptor antagonist which has been clinically used as an antiemetic at the time of administering anti-tumor drug; PA1 a selective serotonin S.sub.3 receptor antagonist which has been clinically used as an antiemetic at the time of administering anti-tumor drug; PA1 a drug which has been used world-wide as an antiemetic or gastrointestinal motility improving agent chemical name: 4-amino-5-chloro-N-2-(diethylamino)ethyl!-2-methoxybenzamide dihydrochloride monohydrate; cf. eg., Merck Index, 11th ed. 6063 (1989)!.
and also discloses that Het can stand for pyridyl. Whereas, a sole specific compound in which Het is 3-pyridyl group and which is disclosed in the specification is the one of Example 37, represented by the formula below: ##STR3## This compound of Example 37 clearly differs in structure from the compound of the present invention which is expressed by the later presented formula (I). In the former compound, 3-pyridyl group is unsubstituted and 4-position of hexahydro-1H-1,4-diazepine is substituted with methyl.
Said KOKAI Gazette, furthermore, teaches that the compounds of above formula (A) are serotonin S.sub.3 (5-HT.sub.3) receptor antagonists and are useful for therapeutic and prophylactic treatments of anorexia, nausea, emesis, abdominal fullness and the like accompanying acute and chronic gastritis, and such diseases as gastric and duodenal ulcer; or of nausea or emesis occurring with administration of anti-tumor agents, radioactive irradiation and motion sickness. The Gazette, however, is silent on their dopamine D.sub.2 receptor antagonism.
Furthermore, WO93/08186 discloses a group of compounds represented by formula (B) below: ##STR4## in which R.sub.1 stands for C.sub.1-6 alkoxy, C.sub.3-8 cycloalkoxy or C.sub.3-8 cycloalkyl C.sub.1-4 alkoxy; R.sub.2 stands for hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or amino which may be substituted with 1 or 2 C.sub.1-6 alkyl; R.sub.3 stands for hydrogen, halogen or C.sub.1-6 alkyl; L is O or NH; and Z stands for di-azacyclic or azadicyclic side chain),
teaching that said compounds are useful for therapeutic or prophylactic treatments of pain, emesis, central nervous system disorder and gastrointestinal disorder, as 5-HT.sub.3 antagonists.
Said WO93/08186 cites, as one of adequate examples of di-azacyclic side chain Z. EP-A-358903 belonging to the patent family of afore-cited KOKAI Patent Application, KOKAI No. 92959/93, but contains no specific disclosure on a compound having a di-azacyclic side chain which is covered by the general formula (A) as above. Thus. WO93/08186 does not at all suggest the compound of the present invention.
On the other hand, domperidone chemical name: 5-chloro-1-1-3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl!-4-piperid inyl!-1,3-dihydro-2H-benzimidazol-2-one; cf. eg. Merck Index, 11th ed. 3412 (1989)! which is a dopamine D.sub.2 receptor antagonistic agent, is effective to alleviate emesis accompanying various troubles of the digestive system and that accompanying infantile cold syndrome, but exhibits only insufficient effect on emesis occurring upon administration of anti-tumor agents such as cisplatin.
Recently, as a drug which can selectively and strongly inhibit the emesis occurring with administration of anti-tumor agents, serotonin S.sub.3 receptor antagonistic agent has been developed, and currently such antiemetic agents as granisetron hydrochloride chemical name: endo-1-methyl-N-(9-methyl-9-azobicyclo-3.3.1!non-3-yl)-1H-indazole-3-carb oxamide hydrochloride; cf. eg., Merck Index, 11th ed. 4443 (1989)!, ondansetron hydrochloride (chemical name: 1,2,3,9-tetrahydro-9-methyl-3-(2-methyl-1H-imidazol-1-yl)methyl!-4H-carba zol-4-one hydrochloride; cf. eg., Merck Index, 11th ed., 6802 (1989)! and azasetron hydrochloride chemical name: (+)-N-1-azabicyclo-2.2.2!oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzoxazine-8-carboxamide hydrochloride; cf. eg., Drugs of the Future, 18(3), 206-211 (1993)! are clinically used. However, clinical application of these serotonin S.sub.3 receptor antagonists is limited to the emesis mainly occurring in occasions of administration of anti-tumor agents. They furthermore are said to exhibit only insufficient effect on late emesis.
Thus, while drugs effective on specific type of emesis do exist, an antiemetic agent of wide application range which can strongly inhibit emesis induced by various causes has not yet been developed. Hence development of an antiemetic agent having a broad spectrum has been in demand.